Result: However, recently, it has been observed that CPSF6 only redistributes to nuclear speckles during WT HIV-1 infection and not during infection with CPSF6-binding deficient mutants A77V and N74D.
Discussion: Furthermore, unlike WT HIV-1, neither the N74D nor the A77V mutant can re-localise CPSF6 to nuclear speckles, showing that this is a CA dependent event.
Discussion: Interestingly, studies with the CPSF6 binding-defective HIV-1 CA mutants, N74D and A77V, have reported that a longer residence time at the nuclear envelope promotes integration into heterochromatin regions close to the nuclear envelope.
MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface.
Discussion: Direct recruitment of wild type CA, and not CA N74D, by MxB is the simplest explanation for these data.
Discussion: Furthermore, HIV-1 bearing the CPSF6 binding mutant N74D was MxB insensitive, but CPSF6 depletion, which has a similar effect on HIV-1 as N74D mutation in terms of cofactor dependence and integration targeting, did not render HIV-1 R9 GFP MxB insensitive.
Discussion: Mutation N74D replaces the amide side chain with a negatively charged acidic side chain in close spatial proximity to the positively charged K70 (Figure 6:figure supplement 1).
Discussion: We therefore hypothesise that N74D conformationally alters this region of the capsid to prevent both CPSF6
TRIM34 restricts HIV-1 and SIV capsids in a TRIM5alpha-dependent manner.
Abstract: Through an unbiased screening approach, called HIV-CRISPR, we show that the CPSF6-binding deficient, N74D HIV-1 capsid mutant is sensitive to restriction mediated by human TRIM34, a close paralog of the well-characterized HIV restriction factor TRIM5alpha.
Abstract: Through immunofluorescence studies, we show that TRIM34 and TRIM5alpha colocalize to cytoplasmic bodies and are more frequently observed to be associated with infecting N74D capsids than with WT HIV-1 capsids.
Introduction: Further, both the HIV-1 P90A capsid mutant and the HIV-1 N74D capsid mutant, referred to hereafter as P90A and N74D respectively, have been shown to be hyp
Frequency of capsid substitutions associated with GS-6207 in vitro resistance in HIV-1 from antiretroviral-naive and -experienced patients.
PMID: 32154864
2020
The Journal of antimicrobial chemotherapy
Abstract: METHODS: Plasma samples from ART-naive or -experienced PLWH, including PI-experienced people, were sequenced and analysed for the presence of capsid variants identified during in vitro resistance selection: L56I, M66I, Q67H, K70N, N74D, N74S and T107N.
Characterization of HIV-1 uncoating in human microglial cell lines.
Abstract: Viruses with capsid mutations N74D and E45A decreased the rate of uncoating in CHME3 cells, but did not alter reverse transcription.
Introduction: We also observed differential uncoating kinetics for the mutant N74D in a HeLa cell line engineered to express TRIM-CypA.
Introduction: We found that the E45A and N74D mutations uncoated slower than wildtype virus, while the mutation A92E uncoated faster than wildtype in OMK cells.
Result: Compared to HIV-GFP, the N74D mutation delayed the process of uncoating and increased the half-life of uncoating to 141 min compared to 62 min for wildtype.
Result: However, if there was a differential effect of cy
The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1.
PMID: 31941344
2020
AIDS research and human retroviruses
Introduction: The binding process includes an interaction with CPSF6 through the CA N-terminal domain (NTD) as well as through the CA C-terminal domain (CTD); specifically, mutations in the respective CA domains, such as N57A or N74D (NTD) or K182R (CTD), have been shown to reduce CPSF6 binding by HIV-1 CA.
Result: On the other hand, the N74D virus, a CPSF6 binding-deficient CA mutant, was not affected by CPSF6-358.
Multiple Pathways To Avoid Beta Interferon Sensitivity of HIV-1 by Mutations in Capsid.
Introduction: Specifically, it was reported that the CypA binding-deficient CA mutant (the P90A mutant) and the CPSF6 binding-deficient CA mutant (the N74D and A105T mutant) are more sensitive than wild-type (WT) CA to IFN alpha (IFN-alpha) in monocyte-derived THP-1 cells.
Discussion: A similar phenotype was observed with N74D and P90A CA mutants in terms of type I IFN hypersensitivity and resistance to MxB.
Discussion: CPSF6 is a host factor that is capable of modulating the
Discussion: also proposed that inappropriate uncoating kinetics might account for the higher type I IFN sensitivity of the N74D virus.
Nup153 Unlocks the Nuclear Pore Complex for HIV-1 Nuclear Translocation in Nondividing Cells.
Abstract: Analysis of integration sites in HIV-1 viruses with N57 mutations revealed diminished integration into transcriptionally active genes in a manner resembling that of HIV-1 in CPSF6 knockout cells or that of HIV-1-N74D.
Single HIV-1 Imaging Reveals Progression of Infection through CA-Dependent Steps of Docking at the Nuclear Pore, Uncoating, and Nuclear Transport.
Result: Also similar to WT viruses, N74D cores co-labeled with INsfGFP and CypA-DsRed docked at the NE and lost the CA marker (n=45.
Result: Also, disappearance of post-uncoating N74D IN complexes at the NE showed a high degree of correlation with productive integration that was virtually identical to correlation observed for disappearing intra-nuclear WT IN complexes (compare Figs.
Result: Analysis of single N74D core docking and uncoating revealed that, interestingly, the loss of CypA-DsRed from after docking was significantly (>3-fold) slower than for WT cores.
Result: However, after uncoating at the NE, N74D IN complexes typically remained colocalized with lamin.
Result: In contrast, post-uncoating PMID: 28727807
2017
PLoS pathogens
Abstract: Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism.
Abstract: Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein.
I
Introduction: Certain CA point mutations, such as N74D, are independent of Nup358, Nup153, CPSF6 and TNPO3 for infection, and show a different integration site selection compared to wild type virus.
Introduction: Compound libraries are screened to find selective hits that inhibit WT more than N74D.
HIV mutation literature information.
PMID: 
2021
PLoS pathogens
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